End-stage liver disease is common in HIV-infected (HIV+) individuals due to co-infection with hepatitis C virus (HCV), hepatitis B virus (HBV), and alcoholic and non-alcoholic fatty liver disease (NAFLD). Liver transplant (LT) in HIV+ individuals provides a clear survival benefit and outcomes will improve further with direct-acting antivirals for HCV. There is already a severe organ shortage, with long waiting times, and a higher waitlist mortality for HIV+ individuals in particular, and the need for LT in HIV+ individuals is expected to grow. Organs from HIV+ deceased donors (HIV D+) are a unique resource for HIV+ transplant candidates. By expanding the donor pool, use of organs from HIV D+ could have a significant public health impact and decrease wait times for all individuals on the waitlist. This motivated the Congressional HOPE (HIV Organ Policy Equity) Act which now allows HIV D+ transplants for HIV+ recipients (R+) under research protocols. Potential risks of HIV D+/R+ transplants include complications related to donor-to-recipient HIV superinfection (HIV-SI), increased organ rejection rates, and accelerated liver fibrosis and/or steatosis after transplant due to viral hepatitis or metabolic liver disease. Experience with HIV D+ LT is extremely limited with only 2 international cases reported and 5 cases in the US performed by our group within a HOPE pilot study. In order to determine if HIV D+ liver transplantation is safe and effective, a prospective multicenter trial is needed. The proposed HOPE in Action Liver Trial will compare outcomes between HIV+ recipients of HIV+ versus HIV- donor livers, enrolling 40 individuals in each group over 3 years at 16 transplant centers. Aim 1 will compare difference in time to major transplant-related and HIV-related complications between the two arms. Aim 2 will compare the incidence of liver disease including HCV- and HBV-related fibrosis and liver steatosis. Mechanistic studies in Aim 3 will characterize HIV-SI in blood and in Aim 4 will characterize both the composition and changes in size of long-lived HIV reservoirs in blood, lymph nodes, and liver longitudinally. A comprehensive digital pathologic repository and a tissue biorepository will be created. We have planned and designed the trial with NIAID-sponsored project team (R34AI23023) and we have assembled a team of experts in Transplant Surgery, HIV/Infectious Diseases, Hepatology, Epidemiology, Biostatistics, Pathology, and Virology. The trial will benefit from existing studies and infrastructure established by our group, including a study of HIV D+ nationally in collaboration with the Organ Procurement and Transplantation Network (R01AI120938) and a Multicenter HOPE in Action Kidney Trial (U01AI134591). In summary, HOPE in Action: A clinical trial of HIV-to-HIV deceased donor liver transplantation will determine whether the use of HIV D+ for LT is safe and effective. In addition, the trial will impact not only the field of organ transplantation, but will also provide new insight into mechanisms of HIV-related liver disease, HIV superinfection, and will directly inform HIV cure research efforts.